A novel repressor, par-4, modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1

The tumor suppressor WT1 represses and activates transcription, The loss and/or imbalance of the dual transcriptional activity of WT1 may contribute to Wilms' tumor, In this study, we identified par-4 (for prostate apoptosis response) as a WT1-interacting protein that itself functions as a transcriptional repressor, par-4 contains a putative leucine zipper domain and is specifically upregulated during apoptosis of prostate cells (S. F. Sells, D. P. Wood, Jr., S. S. Joshi-Barve, S. Muthukkumar, R. J. Jacob, S. A. Crist, S. Humphreys, and V. M. Rangnekar, Cell Growth Differ. 5:457-466, 1994). The leucine repeat domain of par-4 was shown to interact with the zinc finger DNA binding domain of WT1, Immunoprecipitation-Western blot (immunoblot) analyses demonstrated in vivo WT1-par-4 interactions, par-4 was ubiquitously expressed, and the protein was found in both the nucleus and the cytoplasm, Functionally, par-4 inhibited transcription activated by WT1, but not by the related protein EGR1, Inhibition of WT1-mediated transcription was dependent on the domain of par-4 that mediates its physical association with WT1. In addition, par-4 augmented WT1-mediated repression, possibly by contributing an additional repression domain, Consistent,vith these results, par-4 functioned as a transcriptional repressor when brought to a promoter via a heterologous DNA binding domain, Significantly, par-4, but not a mutant unable to interact with WT1, rescued growth suppression caused by WT1. Thus, we identified a novel repressor that modulates transcription as well as growth suppression functions of WT1.